The islet microenvironment can be affected by infiltrating innate immune cells and lymphocytes, which can lead to beta cell malfunction or destruction and, hence, clinical diabetes. The exact cellular component releasing inflammatory signals in the islet to activate the immune cells is unknown. Based on our previous observation that islet mesenchymal stem cells (MSCs) derived from non-obese diabetic (NOD) mice could release exosomes that are highly immunostimulatory, we propose that MSC-released exosomes are a novel inflammatory and autoimmune trigger in the islets. Depending on genetic and environmental factors, exosome contents may vary and result in different functions and immune responses. We hypothesize that diabetes-associated genes and environmental factors may cause MSCs to release pro-inflammatory exosomes that lead to beta cell malfunction and autoimmunity. We will study islet-derived MSCs and exosomes from mouse strains with different susceptibility to diabetes to examine the genetic contribution to exosome heterogeneity and the effects on immune responses to exosomes. High-fat diet and inflammatory cytokines will be tested as environmental factors that could stimulate the MSCs and affect exosome secretion. By analyzing the antigens and RNA sequences expressed in exosomes, we expect to identify candidate biomarkers or signals that are unique to NOD exosomes and may play a role in causing islet inflammation and autoimmunity.